Bottom Line:
Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans.In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines.A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

ABSTRACTIn the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

Fig2: Expression of ASIP in full, dermal, and epidermal layers of skin. a Plot of eQTL analysis on ASIP, where expression of ASIP is strongly associated with pigmentation variants rs17305573, rs910873 and rs1885120 in skin full-layer biopsy samples. bASIP is exclusively expressed in the dermal layer of skin, and not in the epidermal layer of skin (nd not detected). Samples derived from the dermal layer are denoted with ‘D’, samples derived from the epidermal layer are denoted with ‘E’. Sample 1 has the rs1885120-CC genotype, with a dark skin phenotype, sample 2 has the rs1885120-CC genotype, with a light skin phenotype, sample 3 has the rs1885120-CT genotype, with a light skin phenotype

Mentions:
To further investigate the expression patterns of the 22 genes at 20q11.22 and their (potential) correlation with pigmentation-SNP genotypes, we checked the expression quantitative trait locus (eQTL) data in the publically available Multiple Tissue Human Expression Resource (MuTHER) Study database (Nica et al. 2011). We found for skin biopsy samples a highly significant association between the expression of ASIP (HumanHT-12 array probe ILMN_1791647 targeting exon 3 of ASIP) and the SNPs rs1885120, rs910873 and rs17305573 (p value = 1 × 10−26) (Fig. 2a; Table S9), while for the expression of 8 genes at 20q11.22 (EIF2S2, ITCH, MAP1LC3A, GGT7, EDEM2, PROCR, EIF6, and FAM83C of which EIF2S2, ITCH, MAP1LC3A, EDEM2, PROCR and EIF6 were highlighted by at least one of our previous expression analyses) more modest associations with SNP genotypes were found. For these 8 genes, the expression-associated SNPs resulting from the eQTL analysis do, however, not overlap with our GWAS results (Table S9). Notably, in the MuTHER project, full-layer skin samples were used while in our study only epidermal samples were applied. The difference between our data and that obtained with the MuTHER-eQTL analysis might therefore be explained by expression of ASIP in the skin dermis rather than in the melanocytes or keratinocytes located in the skin epidermis.Fig. 2

Fig2: Expression of ASIP in full, dermal, and epidermal layers of skin. a Plot of eQTL analysis on ASIP, where expression of ASIP is strongly associated with pigmentation variants rs17305573, rs910873 and rs1885120 in skin full-layer biopsy samples. bASIP is exclusively expressed in the dermal layer of skin, and not in the epidermal layer of skin (nd not detected). Samples derived from the dermal layer are denoted with ‘D’, samples derived from the epidermal layer are denoted with ‘E’. Sample 1 has the rs1885120-CC genotype, with a dark skin phenotype, sample 2 has the rs1885120-CC genotype, with a light skin phenotype, sample 3 has the rs1885120-CT genotype, with a light skin phenotype

Mentions:
To further investigate the expression patterns of the 22 genes at 20q11.22 and their (potential) correlation with pigmentation-SNP genotypes, we checked the expression quantitative trait locus (eQTL) data in the publically available Multiple Tissue Human Expression Resource (MuTHER) Study database (Nica et al. 2011). We found for skin biopsy samples a highly significant association between the expression of ASIP (HumanHT-12 array probe ILMN_1791647 targeting exon 3 of ASIP) and the SNPs rs1885120, rs910873 and rs17305573 (p value = 1 × 10−26) (Fig. 2a; Table S9), while for the expression of 8 genes at 20q11.22 (EIF2S2, ITCH, MAP1LC3A, GGT7, EDEM2, PROCR, EIF6, and FAM83C of which EIF2S2, ITCH, MAP1LC3A, EDEM2, PROCR and EIF6 were highlighted by at least one of our previous expression analyses) more modest associations with SNP genotypes were found. For these 8 genes, the expression-associated SNPs resulting from the eQTL analysis do, however, not overlap with our GWAS results (Table S9). Notably, in the MuTHER project, full-layer skin samples were used while in our study only epidermal samples were applied. The difference between our data and that obtained with the MuTHER-eQTL analysis might therefore be explained by expression of ASIP in the skin dermis rather than in the melanocytes or keratinocytes located in the skin epidermis.Fig. 2

Bottom Line:
Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans.In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines.A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

ABSTRACTIn the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.